Methods of treating estrogen-responsive conditions by orphan nuclear receptor activation

Abstract

The invention provides a method of treating an estrogen responsive condition comprising administration of an agonist of an orphan nuclear receptor, wherein activation of the orphan nuclear receptor inhibits estrogen activity. The invention also provides a method of reducing the size of an estrogen responsive tumor comprising administration of an agonist of an orphan nuclear receptor, wherein activation of the orphan nuclear receptor inhibits estrogen activity. The invention also provides a pharmaceutical composition comprising an agonist of an orphan nuclear receptor and a pharmaceutically acceptable vehicle, wherein activation of the orphan nuclear receptor inhibits estrogen activity.

1 . A method of reducing the size of an estrogen responsive tumor comprising administering an agonist of an orphan nuclear receptor, wherein activation of the orphan nuclear receptor inhibits estrogen activity.  
     
     
         2 . The method of  claim 1 , wherein the estrogen responsive tumor is associated with a condition selected from the group consisting of breast cancer, lung cancer, uterine cancer, and prostate cancer.  
     
     
         3 . The method of  claim 1 , wherein the nuclear receptor is selected from the group consisting of Liver X Receptors (LXR) and glucocorticoid receptors (GR).  
     
     
         4 . The method of  claim 3 , wherein the Liver X Receptor is selected from the group consisting of LXRα and LXRβ.  
     
     
         5 . The method of  claim 4 , wherein the agonist is selected from the group consisting of GW3965, TO1317 (T0901317) and 22(R)-hydroxycholesterol.  
     
     
         6 . The method of  claim 3 , wherein the nuclear receptor is GR, and wherein the agonist is a GR agonist.  
     
     
         7 . The method of  claim 6 , wherein the agonist is selected from the group consisting of dexamethasone, ZK216348, RU28363, cortisol, prednisone, and prednisolone.  
     
     
         8 . The method of  claim 1 , comprising administration of a first agonist of a first orphan nuclear receptor, and administration of a second agonist of a second orphan nuclear receptor, wherein the first agonist is different from the second agonist.  
     
     
         9 . The method of  claim 8 , wherein the first orphan nuclear receptor is different from the second orphan nuclear receptor.  
     
     
         10 . The method of  claim 8 , wherein the first orphan nuclear receptor is LXR and the second orphan nuclear receptor is GR.  
     
     
         11 . The method of  claim 10 , wherein the first agonist is GW3965 and the second agonist is dexamethasone.  
     
     
         12 . The method of  claim 1 , further comprising administration of chemotherapy.  
     
     
         13 . The method of  claim 12 , wherein the chemotherapy is selected from the group consisting of an antiestrogen, an aromatase inhibitor, and a cytotoxic chemotherapy.  
     
     
         14 . The method of  claim 12 , wherein the chemotherapy comprises an antiestrogen selected from the group consisting of tamoxifen, toremifene, raloxifene, droloxifene, idoxifine, nafoxidine, levomeloxifene, clomiphene, CI-680, CI-628, CN-55,956-27, MER-25, U-11,555A, U-11,100A, ICI-46,669, ICI-46,474, diphenolhydrochrysene, erythro-MEA, Parke Davis CN-35,945, allenolic acid, cyclofenil, ethamoxytriphetol, triparanol.  
     
     
         15 . The method of  claim 12 , wherein the chemotherapy comprises an aromatase inhibitor selected from the group consisting of letrozole, anastrozole, exemestane, raloxifene, fadrozole, lentaron, formestane, rivizor, vorozole, and fulvestrant.  
     
     
         16 . The method of  claim 12 , wherein the chemotherapy comprises a cytotoxic chemotherapy selected from the group consisting of methotrexate, cyclophosphamide, 5-flurouracil, doxorubicin, paclitaxel, and docetaxel.  
     
     
         17 . The method of  claim 1 , wherein the agonist is administered as an adjuvant therapy to surgery.  
     
     
         18 . A method of treating an estrogen responsive condition comprising administration of an agonist of an orphan nuclear receptor, wherein activation of the orphan nuclear receptor inhibits estrogen activity.  
     
     
         19 . The method of  claim 18 , wherein the estrogen responsive condition is selected from the group consisting of breast cancer, lung cancer, uterine cancer, and prostate cancer.  
     
     
         20 . A pharmaceutical composition comprising an agonist of one or more nuclear receptors and a pharmaceutically acceptable vehicle, wherein the nuclear receptor is an inhibitor of estrogen activity.  
     
     
         21 . The composition of  claim 20 , wherein the nuclear receptor is selected from the group consisting of Liver X Receptors (LXR) and glucocorticoid receptors (GR).  
     
     
         22 . The composition of  claim 21 , wherein the Liver X Receptor is selected from the group consisting of LXRα and LXRβ.